The Barraquer-Simons syndrome, APL or cephalothoracic
lipodystrophy, was described by the Spanish physician Barraquer in 1906
and the German physician Simons in 1911 [1].

There were reported only 255 cases since then. It is characterized
by progressive and symmetrical loss of adipose tissue in craniocaudal
direction, starting with the face and progressively involving the trunk,
arms and legs up to the thighs. However, arms and legs are rarely
affected.

The adipose stores of the gluteal regions and lower extremities
(including soles) tend to be either preserved or increased, particularly
among women [2].

The onset of the disease often occurs in the first and second
decade of life, predominantly affecting females, with a ratio of 4:1 to
males [3].

The determinant cause of Barraquer-Simons disease has not yet been
elucidated. The only aspect it has been agreed on is that it is not an
inherited disorder in the classic mendelian sense; it rather represents
a phenotype with a complex etiology [4].

Case report

We present the case of TDE, a female patient of 68-year old with
Barraquer-Simons disease diagnosed in the second decade of life. The
patient is the fourth child of healthy non-consanguineous parents.
During the first 3 months of pregnancy, her mother drunk an anti-malaric
substance called chinin in the attempt to abort the baby. The attempt
failed and she was born apparently healthy.

At the age of 7 she was diagnosed with situs inversus totalis
during a chest radiological checkup required for entering the first
grade. At 15 years old the loss of fat from the body upper part was
already visible and she was diagnosed with nodular goiter and APL.
Severe systemic hypertension was found at 32 years of age and idiopathic
hepatitis at 35. At 61 she already had diabetes mellitus type 2, being
on insulin in the last three years.

At 65-year old doctors have found her with positive serum markers
for reumathoid artrithis and she was also diagnosed with osteoporosis
based on DEXA scan and polymiositis. A muscle disease was suggested by
her sudden partial painful contractions to the abdomen or limbs,
especially to the lower ones, so she suffered a muscle biopsy and the
diagnosis was issued based on the pathological study.

The patient had 6 pregnancies, with 4 abortions (2 natural and 2
required ones) and 2 children, normally delivered and breast feeded; she
has now 5 grandchildren, all in good health. The family medical history
is irrelevant, none of her siblings having been diagnosed with
Barraquer-Simons disease or other metabolic conditions. She worked as a
farmer and denies smoking or drinking alcohol.

TDE is a chronic patient of the Clinical Hospital of Rehabilitation
in Iasi. Her last admittance was in September 2013 for shortness of
breath, productive coughing with mucopurulent sputum and generalized
joint pain. Physical examination revealed loss of adipose tissue in the
upper part of the body, with complete facial fat atrophy, pseudo
hypertrophy of the muscular mass and hirsutism. Comparing Figures 1, 2
and 3, we can see that these features have progressed along the years.

Examination of the articular system has revealed joint pains mainly
in the cervical and sacro-iliac region, painful hands and feet,
especially in the night, with decreased range of motion and
characteristic deformities for rheumatoid arthritis; the Patrick
maneuvers were bilateral positive.

Thorax examination showed bilateral basal dry crackles and dullness
to the left base. Systemic blood pressure was around 140/70 mmHg and
heart rate 60 beats/min. A strong systolic heart murmur was audible in
all areas of auscultation with a maximum of 6/6 intensity in the mitral
and aortic areas.

The liver was palpable at 10 cm under the left costal margin and
the spleen at 3 cm under the right one. The liver and spleen were
spontaneously and at palpation sensitive.

The pathological results of laboratory tests are shown in Table 1.
Normal range values are delivered by the Rehabilitation Clinical
Hospital's Laboratory.

The ECG registration on the right hemithorax placement (Figure 4)
has shown a right QRS axis deviation at 120 degrees, an important left
ventricular hypertrophy with a Sokolow Lyon index of 86 mm (in the
precordial leads, there is a special registration with 5 mm standing for
1mV) and inverted T waves from V3 to V6, as well in DIII and aVF. The
chest X-ray showed dextrocardia, cardiomegaly, pulmonary congestion and
aortic atheromatosis (Figure 5).

The abdominal ultrasonography revealed intense hepatic steatosis,
small stones and bilateral double kidney, while the thyroid ultrasound
examination discovered same old multiple nodules.

Scientists found that both patients with APL and obese patiens have
severe insulin resistance, dyslipidemia, hepatic steatosis and features
of hyperandrogenism, as shown in the presented case.

This illustrates a complex relationship between metabolic health
and the fat mass. An explanation would be that adipocytes not only store
fat but also secrete a variety of bioactive proteins into circulation.

Leptin controls delivery of free fatty acids into adipocytes and
limits the delivery of free fatty acids to nonadipocytes (liver and
muscle cells), thus protecting nonadipocytes from lipotoxicity. Leptin
deficiency results in an increase in exposure of muscle cells to free
fatty acids and allows uptake of free fatty acids for oxidation and
energy utilization, resulting in insuline resistance [6].

In studies done on human aortic endothelial cells, adiponectin has
been shown to dose-dependently decrease the surface expression of
vascular adhesion molecules known to modulate endothelial inflammatory
responses [7]. It also inhibits proliferation of vascular smooth muscle
cells [8] and concentrates within the vascular intima of
catheter--injured vessels [9]. In clinical studies, low adiponectin
levels have been associated with an atherogenic lipid profile [5].

This theory is backed up by experimental work on mice. The
peroxisome proliferator-activated receptor gamma (PPARG) P465L mouse
model is the equivalent human variant of partial lipodystrophy. PPARG is
a member of the nuclear hormone receptor superfamily and is highly
expressed in adipose tissue, monocytes, macrophages, colon and at lower
levels in multiple other tissues. It plays a critical role in adipocyte
differentiation.

These mice have APL features, but do not express insulin resistance
unless crossed with severely hyperphagic leptin-deficient ob/ob mice.
This shows the key role that leptin plays in the onset of diabetes.

Another experiment has used transgenic mice overexpressing
adiponectin. When crossed with obese mice, these mice become even more
obese and yet manifest significantly improved metabolic homeostasis,
suggesting that if adipose tissue can expand to accommodate surplus
calories, insulin resistance can be ameliorated [7].

Starting from these findings, treatment perspectives for metabolic
diseases were developed. Some of them have passed clinical trials, like
inhibitors of protein tyrosine phosphatase 1B (PTP1B), while others only
showed efficiency on mice, like adiponectin natural stimulants,
adiponectin receptors agonists or fat transplantation.

PTP1B regulates the insulin and leptin signaling pathways.
Inhibition of this enzime controls appetite and blood sugar levels. The
lead compound in this series is known as MSI-1436 (trodusquemine) which
completed in 2009 phase 1 of clinical trials and has demonstrated
dose-dependent weight loss and glucose control even after a single dose
[10].

An adiponectin natural stimulant is found in the turmeric plant.
Curcumin is one of the principal anti-inflammatory and healthful
components of turmeric comprising 2-8% of most turmeric preparations.
Studies have shown that it induces the expression of adiponectin and
also has effects to inhibit adipocyte differentiation and to promote
antioxidant activities [11].

The orally active synthetic small-molecule AdipoRon bounds to both
AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to
adiponectin in muscle and liver, such as activation of AMPK and
PPAR-[alpha] pathways, and ameliorated insulin resistance and glucose
intolerance in mice fed with a high-fat diet, which was completely
obliterated in AdipoR1 and AdipoR2 double-knockout mice.

An alternative strategy to relieving metabolic stress on diseased
adipose tissue would be to provide extra fat depots.

In 2011, Dr. Laurie Goodyear and colleagues transplanted brown fat
from mice of a normal weight into mice fed with a standard or high-fat
diet.

Eight to 12 weeks after transplantation, the mice fed a normal diet
showed improved glucose tolerance, increased insulin sensitivity, lower
body weights and decreased fat mass. Meanwhile, mice given a
'fake' transplant of glass or beads did not show any
improvement, proving this way the efficacy of brown fat [13].

Also, transplantation of normal fat on mice with generalized
lipodystrophy has reversed hyperglycemia, together with dramatical
reduceding in plasma insulin levels and hepatic steatosis [14].

Conclusion

It is important to study rare diseases such as the Barraquer-Simons
syndrome, because they can reveal valorous insights on human metabolism
and generate treatment perspectives not only for their management, but
also for the most challenging diseases of our century. An intervention
of fat transplantation might be considered as a therapeutical approach
for our APL patient in the future.

Received: August 2014; Accepted after review: September 2014;
Published: September 2014